Experimental and Clinical Psychopharmacology Genetic Influences on Delayed Reward Discounting: A Genome-Wide Prioritized Subset Approach James MacKillop, Joshua C. Gray, Jessica Weafer, Sandra Sanchez-Roige, Abraham A. Palmer, and Harriet de Wit Online First Publication, September 27, 2018. http://dx.doi.org/10.1037/pha0000227 CITATION MacKillop, J., Gray, J. C., Weafer, J., Sanchez-Roige, S., Palmer, A. A., & de Wit, H. (2018, September 27). Genetic Influences on Delayed Reward Discounting: A Genome-Wide Prioritized Subset Approach. Experimental and Clinical Psychopharmacology. Advance online publication. http://dx.doi.org/10.1037/pha0000227 Experimental and Clinical Psychopharmacology © 2018 American Psychological Association 2018, Vol. 1, No. 999, 000 1064-1297/18/$12.00 http://dx.doi.org/10.1037/pha0000227 Genetic Influences on Delayed Reward Discounting: A Genome-Wide Prioritized Subset Approach James MacKillop Joshua C. Gray McMaster University/St. Joseph’s Healthcare Hamilton and University of Georgia and Brown University Homewood Research Institute, Guelph, Ontario, Canada Jessica Weafer Sandra Sanchez-Roige and Abraham A. Palmer University of Chicago University of California, San Diego Harriet de Wit University of Chicago Delayed reward discounting (DRD) is a behavioral economic measure of impulsivity that has been consis- tently associated with addiction. It has also been identified as a promising addiction endophenotype, linking specific sources of genetic variation to individual risk. A challenge in the studies to date is that levels of DRD are often confounded with prior drug use, and previous studies have also had limited genomic scope. The current investigation sought to address these issues by studying DRD in healthy young adults with low levels of substance use (N ϭ 986; 62% female, 100% European ancestry) and investigating genetic variation genome-wide. The genome-wide approach used a prioritized subset design, organizing the tests into theoret- ically and empirically informed categories and apportioning power accordingly. Three subsets were used: (a) a priori loci implicated by previous studies; (b) high-value addiction (HVA) markers from the recently developed SmokeScreen array; and (c) an atheoretical genome-wide scan. Among a priori loci, a nominally significant association was present between DRD and rs521674 in ADRA2A. No significant HVA loci were detected. One statistically significant genome-wide association was detected (rs13395777, p ϭ 2.8 ϫ 10Ϫ8), albeit in an intergenic region of unknown function. These findings are generally not supportive of the previous candidate gene studies and suggest that DRD has a complex genetic architecture that will require considerably larger samples to identify genetic associations more definitively. Public Health Significance Steep discounting of future rewards has been substantially associated with addiction and other psychiatric disorders. Increasing evidence implicates genetic influences, but most previous studies have had relatively small sample sizes, limited genomic scope, and potentially confounding levels of previous substance use. This study addresses these issues and finds further evidence for one previously reported genetic association and a novel genome-wide association, further elucidating genetic contributions to this form of impulsivity. Keywords: decision making, delayed reward discounting, genetics, genomics, impulsivity Supplemental materials: http://dx.doi.org/10.1037/pha0000227.supp This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. acknowledge the outstanding contributions of the research staff in execut- James MacKillop, Peter Boris Centre for Addictions Research, McMas- ing the reported research including the bioinformatics support of Kyle ter University/St. Joseph’s Healthcare Hamilton, and Homewood Research Hernandez at the University of Chicago and are grateful for access to the Institute, Guelph, Ontario, Canada; Joshua C. Gray, Department of Psy- SmokeScreen loci from James Baurley. This article was supported in part chology, University of Georgia, and Department of Psychiatry and Human by National Institutes of Health Grant R01DA032015 and by the Peter Behavior, Brown University; Jessica Weafer, Department of Psychiatry Boris Chair in Addictions Research. The funding source had no other role and Behavioral Neuroscience, University of Chicago; Sandra Sanchez- other than financial support. The content is solely the responsibility of the Roige, Department of Psychiatry, University of California, San Diego; authors and does not necessarily represent the official views of the National Abraham A. Palmer, Department of Psychiatry and Institute for Genomic Institutes of Health. No authors have potential conflicts of interest to Medicine, University of California, San Diego; Harriet de Wit, Department declare, with the exception of James MacKillop who discloses that he is a of Psychiatry and Behavioral Neuroscience, University of Chicago. principal in BEAM Diagnostics, Inc. These findings were previously reported at a symposium at the annual Correspondence concerning this article should be addressed to James meeting of the American College of Neuropsychopharmacology. MacKillop, Peter Boris Centre for Addictions Research, McMaster Uni- All authors made substantive contributions to the research reported, and versity/St. Joseph’s Healthcare Hamilton, 100 West 5th Street, Hamilton all authors have read and approved the final manuscript. The authors Ontario L8P 3R2, Canada. E-mail: [email protected] 1 2 MACKILLOP ET AL. Delayed reward discounting (DRD) refers to the extent to which proximal to the dopamine (DA) D2 receptor gene, DRD2. Varia- an individual devalues a reward based on its delay in time (Bickel tion in DRD has also been reported in association with another & Marsch, 2001; Bickel, Johnson, Koffarnus, MacKillop, & Mur- DA-related locus in COMT (rs4680; Boettiger et al., 2007; Gianotti, phy, 2014). It is a behavioral economic measure of impulsivity, Figner, Ebstein, & Knoch, 2012; MacKillop et al., 2015), which and is also referred to as impulsive choice, intertemporal choice, encodes catechol-O-methyl transferase, the enzyme involved in me- and capacity to delay gratification. Typically, DRD is operation- tabolizing DA in the prefrontal cortex (Chen et al., 2004; Tunbridge, ally defined by how much a person prefers smaller immediate Bannerman, Sharp, & Harrison, 2004). Finally, DRD has also been rewards versus larger delayed rewards on experimental tasks, with reported to be associated with variants in genes contributing to sero- more precipitous devaluation of future rewards reflecting greater tonergic and nor-adrenergic activity (Havranek, Hulka, & Tasiudi, impulsivity. Numerous studies have shown that individuals with 2017; Sonuga-Barke et al., 2011). addictive disorders exhibit steeper DRD than controls (Bickel, However, the existing literature on genetic correlates of DRD Odum, & Madden, 1999; Coffey, Gudleski, Saladin, & Brady, has a number of limitations. To start, the samples have typically 2003; MacKillop, Anderson, Castelda, Mattson, & Donovick, been small, mainly permitting analyses focusing on single can- 2006; Madden, Petry, Badger, & Bickel, 1997; Petry, 2001). didate genes or a few biologically related loci. Further, the Significant associations have also been reported using dimensional samples have been heterogeneous. Across studies, samples have (continuous) designs (MacKillop et al., 2010, 2014; Murphy & varied from the general population to individuals in recovery Garavan, 2011; Sweitzer et al., 2008). In addition, meta-analyses from alcohol use disorder, individuals with attention-deficit/ of both case–control and dimensional studies have revealed the hyperactivity disorder, gamblers, individuals with cocaine use link between DRD and addiction is robust across studies (Amlung disorder, and smokers. This heterogeneity is a problematic for et al., 2017; MacKillop et al., 2011). These relationships are several reasons. First, it means the study designs are not equiv- distinct from other measures of impulsivity, as DRD tends to be alent and not readily comparable. Second, the inclusion of weakly correlated with other behavioral or self-report measures of individuals with addictive disorders makes it difficult to deter- impulsivity (Caswell, Bond, Duka, & Morgan, 2015; Courtney et mine whether the elevated DRD was a predisposing factor or a al., 2012; Cyders & Coskunpinar, 2011; MacKillop et al., 2014; result of the users’ extended drug exposure. Although several Reynolds, Ortengren, Richards, & de Wit, 2006). This is consistent studies suggest that impulsive DRD in humans predates addic- with the increasing recognition of impulsivity as a multifaceted tive behavior (Audrain-McGovern et al., 2009; Fernie et al., construct comprising conceptually related domains that are quan- 2013; Khurana et al., 2013; Kim-Spoon et al., 2015), there is titatively distinct (de Wit, 2009; Dick et al., 2010; Jentsch et al., also evidence that drug use itself induces more impulsive DRD 2014). (Mendez et al., 2010; Mitchell et al., 2014; Setlow, Mendez, There is considerable evidence that genetic factors influence Mitchell, & Simon, 2009; Simon, Mendez, & Setlow, 2007). addiction (Agrawal & Lynskey, 2008; Goldman, Oroszi, & Ducci, Unsurprising consequences of these limitations